medical management of epilepsy2 sims29!11!15

Medical Management of Epilepsy

Dr R Sridharan MD, DM(Neuro), FRCP(E), FRCP(G), FAAN

Director & Senior Consultant Neurology

Institute of NeuroscienceSIMS Hospitals

Approach to Person With Seizure or Epilepsy

• Exclude seizure mimics• Exclude provoked seizures

(metabolic or other factors)

• Seizure type? (focal vs. generalized)

• Syndrome type?

• Fits in to definition of epilepsy?

Approach to Person With Seizure or Epilepsy

• Evidence of brain pathology or dysfunction?

• Which tests should be obtained?

• Should treatment be started?

• Which drug should be used?

Approach to Person with Epilepsy

• What to do if first AED does not control seizures?

• What to do if person fails 2 or 3 attempts of monotherapy?

• Rational Polytherapy• Medically Refractory Epilepsy & surgery• Attending to comorbidities & QOL• Non drug non surgical treatments

Clinical Approach to Seizure/ Epilepsy

• Diagnosis of epilepsy is clinical supplemented by EEG.

• Ask for description of seizure• Ask for video recording of episode • Make an accurate diagnosis of

epilepsy, seizure type and epilepsy syndrome.

Do Not Start Treatment if Not Sure of Diagnosis

• Mistaking non epileptic seizures for epilepsy• At times non epileptic attacks are even

diagnosed as “Status Epilepticus” and put on ventilator

• “Refractory Seizures” due to inappropriate AED

• Mistaking Epilepsy for Psychogenic seizures

Evaluation of a First Seizure History, physical Blood tests: CBC, electrolytes, glucose,

calcium, magnesium, phosphate, hepatic and renal function, drugs

Lumbar puncture (only if meningitis or encephalitis suspected)

EEG CT or MR brain scan

C-Slide 7American Epilepsy Society 2015

Seizure Precipitants Metabolic and Electrolyte Imbalance Stimulant/other proconvulsant

intoxication Sedative or ethanol withdrawal Sleep deprivation AED noncompliance Hormonal variations Stress Fever or systemic infection Concussion and/or closed head injury


Treatment based on risk of Sz Recurrence

Recurrence After First Unprovoked Seizure in Adults

• Chance for a recurrent seizure is greatest within the first 2 years after a first seizure (21%45%) (Level A).

• Increased risk for seizure recurrence with– prior brain insult such as a stroke or trauma

(Level A),

– EEG with epileptiform abnormalities (Level A), – Significant brain-imaging abnormality (Level B),– Nocturnal seizure (Level B).

Slide 10AAN/ AES Guidelines: Management of an Unprovoked First Seizure in Adults 2015

First Seizure: Recommendations for Rx

• Immediate AED therapy, reduces the risk for a seizure recurrence in the subsequent 2 years (Level B); it may not improve QOL (Level C).

• Over the longer term (> 3 years) immediate AED treatment is unlikely to improve the prognosis for sustained seizure remission (Level B).

• Risk for AED AEs ranges from 7% to 31% (Level B); - predominantly mild and reversible, except for rare Steven Johnson’s .

Slide 11

AAN/ AES Guidelines: Management of an Unprovoked First Seizure in Adults 2015

Treating I Seizure – Other Indications

• Focal Seizure• Onset with Status Epilepticus• Family h/o Epilepsy• High Risk jobs• Person wants to take medication fully aware

of risks and benefits

IES GEMIND Guidelines

Starting Rx after II Sz - GPP• Confirm DiagnosisDiscuss:• Life style modifications – Sleep, driving, hobbies• Likely and rare but impt adverse effects• Lkelihood of success, break through seizures,

need for compliance and risk for status epilepticus if AED is abruptly stopped

• Recording/reporting sz, AEs, precipitants• Emergency management of Sz and use of

concomitant medicationC-Slide 13

Starting Treatment after II Seizure

• Start with single first line AED• Choose the drug best suited for the patient• Start Low – Go Slow• Gradually increase dose till Sz control or

toxicity• Treatment may be deferred if typical febrile Sz,

Rolandic Epilepsy, rare nocturnal sz, provoked Sz

Starting Rx: Monotherapy 60-70% can be controlled with single AED Simplifies treatment Reduces Cost Less adverse effects & Teratogenecity Less drug interactions• Better compliance

C-Slide 15

Conventional AEDs

P-Slide 18

AED Mechanisms of ActionAED

Na+ Channel Blockade

Ca++ Channel Blockade

H-current enhance-ment

Glutamate Receptor Antagonism

GABA Enhance-ment

Carbonic Anhydrase Inhibition

PHT X X (NMDA glycine)

CBZ, OXC X X (CBZ>OXC)

barb, benzo X (GABAA)

ESM X

VPA X X X

FBM X X X (NMDA) X

GBP X X X (NMDA glycine)

LTG X X X (kainate)

TPM X X X (AMPA,kainate) X X

TGB X (reuptake)

LEV X (kainate)

ZNS X X X

PGB X

LCM X (slow inact.)

RUF X

VGB X (metab.)

Modified from White HS and Rho JM, Mechanisms of Action of AEDs, 2010.

American Epilepsy Society 2015

AED CHOICE – Considerations

• Seizure Aggravation• Spectrum of Action of AED• Seizure type (Focal or Gen)• Epilepsy syndrome• Relative efficacy & tolerability• Side effect profile

AED Choice: Considerations• Interaction with other drugs (Comorbids/

Comedication)• Teratogenic Potential• Cost• Rapid loading• Half Life• Patient’s related medical conditions

(beneficial or deleterious – DM, Obesity, Migraine, mood disorders)

• Age. Gender, Occupation, LifestyleC-Slide 20American Epilepsy Society 2015

Seizure Aggravation in Epilepsy Syndromes

Syndrome CBZ PHT GBP LTG VGB BDZ

CAE + + +

JME + + +

LGS + + + +

SMEI + + +

U-L Disease

+

LKS +

Choose a drug that does not aggravate Seizures

Go to Index Slide

AED Choice by Seizure Type & AED Spectrum

Broad-Spectrum AgentsValproateFelbamateLamotrigineTopiramateZonisamideLevetiracetamRufinamide*Vigabatrin*Clobazam*

Narrow-Spectrum AgentsPartial onset seizures

PhenytoinCarbamazepineOxcarbazepineGabapentinPregabalinTiagabineLacosamide*Ezogabine*

AbsenceEthosuximide

C-Slide 23

* New AEDs (approved since 2008)American Epilepsy Society 2015

Prefer Broad Spectrum Agents for Generalized Seizures

Go to Index Slide

AED Choice By Sz Type:

C-Slide 24

Focal Onset Seizures:•Best evidence: CBZ, OXC, PHT,

LEV, ZONI, VPA, LTG, TOPI, PHB, GBP, VGB

•Limited or no data for Monotherapy:

Pregabalin, lacosamide, rufinamide,

ezogabineGlauser T, Ben-Menachem E, Bourgeois B et al. In Epilepsia, 54(3):551-

563, 2013.American Epilepsy Society 2015

AED Choice By Sz Type:

Generalized - Tonic-Clonic Seizures:Best evidence and FDA Indication: VPA, TOPI

Others: Zonisamide, LEV, OXC, PHT, CBZ (may

exacerbate absence and myoclonic sz )

Lamotrigine (may exacerbate myoclonic sz of

symptomatic generalized epilepsies)


Choosing AEDs: Expert Survey

• Survey of 51 opinion leaders- 45 responded• Rated treatments on 1-9 scale: 1=should not

be used; 9=drug of choice• Treatment of choice: >50% of respondents

rated a treatment as 9.• Not Evidence based

Karceski et al. Epilepsy and Behavior 2001;2(Suppl):A1-A50

Seizure Types and AEDs of Choice: Expert survey

Seizure Type I Choice Alternatives

Partial, sec generalied

Carbamazepine, Phenytoin

Valproate,New AEDs

Absence Valproate, ethosuximide

Lamotrigine

Atypical absence/ Atonic

Valproate Lamotrigine

Myoclonic Valproate Lamotrigine, Clonazepam,

GTCS Valproate, Carbamazepine, Phenytoin

Topiramate, Lamotrigine, Zonisamide

Go To Index Slide

AED Choice: Absence Seizures (CAE/JAE)

Best evidence: Ethosuximide (limited spectrum, absence only), VPAAlso shown to be effective: LamotrigineSecond-line: Zonisamide, levetiracetam, topiramate, felbamate, clonazepamMay precipitate or aggravate absence seizures: CBZ, OXC, PHB, PHT, tiagabine, vigabatrin

C-Slide 30

Epilepsy Syndrome


AED Choice: Myoclonic Seizures (JME)

Best evidence: Valproate, Levetiracetam (FDA indication as adjunctive tx), Clonazepam (FDA indication)

Possibly effective: Zonisamide, topiramate

May Precipitate or Aggravate: CBZ, GBP, OXC, PHT, tiagabine, vigabatrin, and possibly lamotrigine (in JME)

C-Slide 31

Epilepsy Syndrome


AED Choice:Lennox-Gastaut Syndrome

Best evidence*: Topiramate, felbamate, clonazepam, lamotrigine, rufinamide, valproate, clobazam* FDA approval is for adjunctive

treatment for all except clonazepam

Some evidence of efficacy: Zonisamide, levetiracetam

C-Slide 32

Epilepsy Syndrome


Sodium Valproate works in most Childhood Epilepsies

Go TO INDEX SLIDE

Head to Head Comparison of AEDs

• Regulatory trials aimed to get the drug licensed for commercial use; Industry Sponsored

• The outcomes with the use of the drug compared to placebo, with analysis of p values

• Often clinically relevant questions are overlooked.• Individual Patient Data Meta-analysis• Pragmatic studies such as SANAD I & Ongoing

SANAD II• Indirect – Multiple Treatment Comparisons

Methodology of Individual Patient Data Meta-analysis

• Identification of RCTs by comprehensive search

• Obtaining data and data verification (randomization, blinding methods, various prognostic factors, EEG,CT, dates of seizures, date and reason for treatment withdrawal)

• Data analysis by intention to treat basis• Stratified log rank test - hazards ratio and

95%CI

Individual Patient Data Meta-Analysis

OUTCOMES ASSESSED:• Time to withdrawal (Retention Time)

(Effectiveness)EFFICACY:• Time to 12 month remission• Time to 6 month remission• Time to first seizure post randomizationMarson AG et al. Carbamazepine versus valproate monotherapy for epilepsy

PHB better than CBZ for time to I Seizure

PHB More Likely to Be Withdrawn cf PHT

CBZ vs VPA: Withdrawal

PHT vs VPA: 12 Month Remission

PHB vs PHT: I seizure

SANAD Study - Partial Epilepsy

• Large RCT (1721 people, 88% partial epilepsy, 10% unclassified)

• Pragmatic design comparing the effectiveness of CBZ vs GBP, LTG, OXC and TPM in the treatment of partial epilepsy.

• Open label — to allow clinicians to determine the optimum rate of titration and dosing regime.

Marson et al SANAD STUDY Lancet 2007;369: 1000-15

SANAD Study – Partial Epilepsy

• CBZ better than GBP, for achieving 12-month remission

• However, there was no significant difference in 12-month remission between CBZ and LTG, CBZ and TOP, CBZ and OXC –Equally Effective

• CBZ - significantly higher risk of treatment failure compared with LTG – Less tolerated

• Marginal differences in efficacy – selectively disseminated by pharma marketing

SANAD Study Generalized Epilepsy

• 716 people, 63% idiopathic generalised 27% unclassified epilepsy) of a pragmatic design that compared VPA, LTG, and TPM

• Treatment failure:– VPA = LTG; VPA better than TPM

• 12 Month Remission:– VPA better than LTG; VPA =TPM

• Marginal differences in efficacy – selectively disseminated by pharma marketing

Marson et al: SANAD STUDY Lancet 2007;369: 1016-26

Multiple Treatment Comparisons

• 20 monotherapy RCTs of 8AEDs• 6418 patients, 4628 with partial Sz• Data synthesized in a single

stratified Cox regression model adjusted for treatment by epilepsy type interactions

Multiple treatment comparisons in epilepsy monotherapy trials Catrin Tudur Smith, Anthony G Marson, David W Chadwick and Paula R Williamson Trials 2007, 8:34 doi:10.1186/1745-6215-8-34

Time to treatment failure – partial Sz

http://www.trialsjournal.com/content/8/1/34/figure/F1

Time to 12 month remission- Partial Sz

Time to I Seizure - Partial Seizures

Time to Treatment Failure – Gen Seizures

Time to 12 Month remission - Gen Seizures

Time to First Sz –Gen Seizures

ILAE Summary Guidelines

C-Slide 52

Seizure type or epilepsy syndrome

Class I

ClassII

ClassIII

Level of efficacy and effectiveness evidence (in alphabetic order)

Adults with partial-onsetseizures

4 1 34 Level A: CBZ, LEV, PHT, ZNSLevel B: VPALevel C: GBP, LTG, OXC, PB, TPM, VGB

Children with partial-onsetSeizures

1 0 19 Level A: OXCLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPA, VGB

Elderly adults with partial-onset seizures

1 1 3 Level A: GBP, LTGLevel B: NoneLevel C: CBZ

Adults with generalizedonset tonic–clonic seizures

0 0 27 Level A: NoneLevel B: NoneLevel C: CBZ, LTG, OXC, PB, PHT, TPM, VPA

Children with generalizedonset tonic–clonic seizures

0 0 14 Level A: NoneLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPA

Children with absenceSeizures

1 0 7 Level A: ESM, VPALevel B: NoneLevel C: LTG

BECTS 0 0 3 Level A: NoneLevel B: NoneLevel C: CBZ, VPA

JME 0 0 1 Levels A, B, C: None

Glauser et al. Epilepsia 2013; 54(3): 551-563.

Return to index


Adverse Effects of AEDs• Type A: Related to mechanism of Action• Type B: Unrelated to known mechanism of

action, unpredictable & occur in susceptible individuals only, irrespective of dosage

• Type C: Chronic toxicity due to cumulative use• Type D: Related to prenatal exposure to the

drug (eg, teratogenesis) or carcinogenesis• Type E: Adverse drug interactions (AED-AED or

AED-non AED)Adverse effects of antiepileptic drugsPiero Perucca, Frank G Gilliam, Lancet Neurology 2012; 11: 792–802

AEDs: Common Adverse Effects

Typically dose-related: TYPE A• Dizziness , Fatigue , Ataxia, Diplopia , GI

Irritability, neuropsychiatric side effects: Levetiracetam, ezogabine

• Word-finding difficulty: Topiramate• Weight loss/anorexia: Topiramate,

zonisamide, felbamate• Weight gain : Valproate (also associated

with polycystic ovarian syndrome ); Carbamazepine, gabapentin, pregabalin


Choice Based on AE Profile?

AEDs: Serious Adverse EffectsTypically Idiosyncratic: Type B

• Renal stones: TOPI, ZONI• Anhydrosis, heat stroke: TOPI,

ZONI• Acute closed-angle glaucoma:

Topiramate• Hyponatremia: CBZ, OXC•Urinary Retention: Ezogabine


AEDs: Serious Adverse EffectsTypically Idiosyncratic: TYPE B

• Aplastic anemia: FELB, ZONI, VPA, CBZ

• Hepatic Failure : VPA, FELB, LTG, PHB

• Peripheral vision loss: VGB • Rash: PHT, LTG, ZONI, CBZ


AED-related rash in adult patients with epilepsy

C-Slide 57

Arif H. et al. Neurology. 2007;68:1701–1709. [PubMed]American Epilepsy Society 2015

▲▲= rash rate significantly greater than average of all other AEDs (p<0.003)▼▼= rash rate significantly lower than average of all other AEDs (p<0.003)▲= trend towards significantly higher than average rash rate of all other AEDs (0.003<p<0.05)▼= trend towards significantly lower than average rash rate of all other AEDs (0.003<p<0.05)

http://www.ncbi.nlm.nih.gov/pubmed/17502552

10th AOEC Singapore 8th Aug 2014

Type C Adverse Effects: Chronic UseEXAMPLES:• Gum hypertrophy, Hirsutism - PHT• Hair loss, Polycystic ovarian disease- VPA• Connective tissue – Dupuytren’s contracture, frozen

shoulder: PHT/PHB• Folate deficiency, Osteopenia, Dyslipidemia with EIAEDs• Visual field loss - Vigabatrine• Depressed mood, irritability – LEV• Thinking problems – TPM, PHB• Changes in weight - VPA, Pregabalin, TPM, Zonisamide• Insomnia – LTG


Type D Adverse Effects: Teratogenesis

• Try to avoid VPA, PHB and polytherapy in women of childbearing potential

• Aim at low risk monotherapy at the lowest effective dose before pregnancy

• Avoid discontinuation or major AED changes during pregnancy

Pregnancy and Epilepsy Guidelines for Management

- 50% of pregnancies in women with epilepsy are unplanned

- All women with epilepsy of reproductive age should be counseled about the effects of epilepsy and AEDs on a future pregnancy

- Pregnancy planning starts with the first AED prescription for a woman of childbearing age and drug changes should be made a year before conception when possible


Type E AEs: AED Drug Interactions• AEDs may affect other drugs• Other drugs affect AEDs• Increase or decrease breakdown• Some other mechanisms for drug interactions• Older drugs viz. PHT, CBZ, PHB induce liver

enzymes, breakdown other drugs, reduce effectivness

• OXC, Topiramate can also be inducers, but to a much lesser extent


Some drugs affected by older AEDs

• Statins• Antipsychotics• Analgesics: Paracetamol, pethidine, opioids• Cancer drugs: Vincristine, Cyclophosphamide• Cardiac drugs: Lasix, Warfarin, digoxin• Immune suppressants: Prednisone, Decadron,

Cyclosporine, Tacrolimus• Antibiotics: doxycycline, itraconazole


AED Interactions:Hormonal Contraception

•Enzyme-inducing AEDs decrease the efficacy of hormonal contraception: CBZ, CLOBA, ESLICAR, FELB, OXC, PERAMPANEL, PHB, PHT, RUFINAMIDE, TOPI• Lamotrigine clearance is increased significantly by

estrogen, particularly synthetic estrogens.• Oral contraceptive pills can decrease lamotrigine levels by up to 50% • Lamotrigine levels may increase significantly during the placebo week

C-Slide 63

IUD is the preferred contraceptive method for women taking enzyme-inducing AEDs.

Gaffield ME et al. Contraception 2011; 83:16–29 .


Possible suicide risk with AEDs• Recent FDA alert (1/2008): Meta-analysis of

199 placebo-controlled add-on tx trials (44,000 patients) - Suicidality with adjunct AEDs than adjunct placebo: 0.43% vs 0.22%; (Extra 2.1 patients per 1000 more patients will have suicidality) “generally consistent across the 11 AEDs”

• Data analysis is controversial and overall difference is very small & Further investigation is needed

• Clinicians should be aware of potential risk and screen for depression/suicidality


Adverse Effects of Valproate vs. other AEDs

0

10

20

30

40

50

60

70

BEHAVIORAL NEUROLOGICAL DIGESTIVE OTHERS

Inci

denc

e of

AE

(%)

VPA

CBZ

PHT

PRM

PB

Adverse Events lower in pts seizure free with monotherapy Return to Inde

x Slide

When the First Drug Fails: Is it Seizure or Epilepsy? Diagnosis of seizure type or syndrome correct?• Progressive pathology?

Avoidable precipitant?

AED appropriate for patient’s seizure– Problem with compliance?– Pharmacokinetic factor?(absorption/ metabolism)– Increase dose?– Change medication – Alternative monotherapy with

an approved drugC-Slide 67American Epilepsy Society 2015

Success in AED Regimens (%)

Rational Polytherapy• When 2 attempts of Monotherapy fail• Synergy (VPA+ LTG)• Different mechanism of action• Broad spectrum, lack of seizure aggravation• Evidence of efficacy, tolerability proven by

meta-analysis or expert consensus• Lack of significant interaction• Pharmacokinetics and side effect profile

Comparison of add-on Efficacy of Newer AEDs

Topiramate more effective compared to other AEDs

Efficacy of Newer AEDs – Add on Treatment

Topiramate, LEV more effective compared to other AEDs -NNT

Tolerability of Newer AEDs -Withdrawals

Topiramate and Oxcarbazepine poorly tolerated

Tolerability of Newer AEDs –Withdrawals from Study

Levetiracetam, Gabapentin, Lamotrigine better tolerated than other AEDs -NNH

CONCLUSIONS FROM ADD-ON STUDIES OF NEWER AEDs

• All newer AEDs are effective compared to placebo

• Topiramate and Levetiracetam >> GBP and VNS?

• No good evidence to choose among the drugs• No long term studies to assess toxicity• Drugs may not have been used at optimal

doses and titration schedules

AEDs: Serum Concentrations AED serum concentrations are to be used as

a guide, not dictate clinical decision making. Serum concentrations are useful when

optimizing AED therapy, assessing compliance, monitoring during pregnancy or oral contraceptive use, or teasing out drug-drug interactions.

Individual patients define their own “therapeutic” and “toxic” ranges.

C-Slide 78Patsalos et al. Epilepsia. 2008;49:1239–1276.


Should Titratable AEDs be preferred?

Discontinuing AEDs >60% chance of successful withdrawal in some

epilepsy syndromes if no Sz >2 years Favorable factors

– Control achieved easily on one drug at low dose– No previous unsuccessful attempts at withdrawal– Normal neurologic exam and EEG– Primary generalized seizures except JME– “Benign” syndrome

Consider relative risks/benefits (e.g., driving, pregnancy)

Practice parameter. Neurology. 1996;47:600–602.


Conclusions-I• Make accurate diagnosis• Optimal Imaging and Investigations• AEDs mainstay of treatment • Monotherapy controls seizures in most people

with partial or generalised epilepsy• Use maximal tolerated doses – drug levels are

only rough guidelines

CONCLUSIONS-II• Aim to achieve complete control of seizures

without unacceptable side effects. • Use a single AED if possible- Monotherapy first

and monotherapy second• There is no good evidence that one drug is

better than another in controlling seizures• All AEDs can cause sedation, dizziness, ataxia

and headache. If patient has side effects, reduce the dose

CONCLUSIONS III• Addition of second line drugs reduces seizure

frequency in people with partial epilepsy who have not responded to usual treatment

• Each additional second-line drug increases the frequency of side effects. There is no good evidence that one second-line drug is better than another

• When patients fail to respond to three drugs, evaluate for possible surgery

• Judge success by QOL

CONCLUSIONS IV• Tailor the treatment to the patients age,

gender, occupation.• Be aware of the patients co-morbidity and

concomitant medications.• Beware of side effects and drug interactions.• When patients are free of seizures for more

than 2 years, consider possiblity of drug withdrawal.

CONCLUSIONS V• Ketogenic and gluten free diet may be useful

for some patients with refractory epilepsy.• Educational interventions, relaxation therapy,

CBT, Yoga, Meditation and family counselling can all improve a patient's psychosocial functioning. But they do not reduce seizure frequency

Thank You

medical management of epilepsy2 sims29!11!15

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